Project Summary Colorectal cancer (CRC) is the second leading cause of cancer death in the industrialized world and the search for susceptibility factors has been a research priority. Affected relative pair studies from the Cancer Genetics Network (CGN), the Colon Neoplasia Sibling Study (CNSS) as well as others have reported genetic regions that are co-inherited more often in first-degree relatives with colorectal cancer (CRC) than those without. A previously unsuspected region on 7q31 was recently identified in the CGN cohort in kindreds with two siblings with CRC (Neklason et al., 2008a). Other studies also found linkages to 9q22.33, 3q21-24, and 11q23 with some minor peaks, including 7q, in agreement across studies (Daley et al., 2008;Djureinovic et al., 2006;Kemp et al., 2006;Neklason et al., 2008a;Wiesner et al., 2003). This supports the paradigm that common inherited colon cancer arises from a number of susceptibility genes of lower penetrance rather than highly penetrant alleles that cause the well described colon cancer syndromes, such as Lynch syndrome or Familial Adenomatous Polyposis. Identifying causative moderate penetrance alleles has been problematic because adequate sample size of kindreds with multiple members with CRC are needed for statistical power. In this application, we plan to address this problem by merging the resources of two large family based studies, CGN and CNSS, and perform a pooled whole genome linkage analysis. In addition, confirmation of the chromosome 7q31 linkage signal will be further analyzed by additional genotyping at 7q in both cohorts. The pooled analysis will include a population of 194 kindreds with colon neoplasias collected by the CNSS study at Case Western University (Daley et al., 2008;Wiesner et al., 2003) and evaluated with the CIDR panel of 389 short tandem repeat (STR) markers, and a population of 83 kindreds of two or more siblings with CRC collected by the CGN and evaluated with 1100 deCODE STR markers (Neklason et al., 2008a). Candidate genes within the 7q31 locus will also be evaluated for alterations in germline DNA and loss of heterozygosity (LOH) in paired normal and tumor DNA. We hypothesize that multiple genetic loci are responsible for familial colorectal cancers;that these genetic loci can be isolated by increasing the statistical power with stratified analysis of affected relative pair populations;and genes with functional changes can be identified within these loci by evaluating the specific populations that link to the loci. PUBLIC HEALTH RELEVANCE: Project Narrative Colorectal cancer (CRC) is the second leading cause of cancer death in the industrialized world and the search for inherited risk factors has been a research priority. This project will combine two large studies of related individuals with colon cancer and precancerous colonic polyps to identify genetic risk factors that are commonly inherited. The project will also focus on better defining a previously identified region on chromosome 7 and examine genes in region for mutations leading to this increased risk.